Dynamic Emergence of Pseudomonas aeruginosa Hypermutation and Ceftazidime-Avibactam Resistance in Acute Systemic Infection

Authors

• PP Khil
• J Ho
• J Youn
• J Lemon
• J Gea-Banacloche
• KM Frank
• RA Bonomo
• JP Dekker

Abstract

P. aeruginosa hypermutators have been frequently in cystic fibrosis patients, where they can facilitate the evolution of antimicrobial resistance. However, the role of P. aeruginosa hypermution in the acute systemic infection remains unclear. In this work, we apply genomic sequencing to 9 serially-collected P. aeruginosa isolates cultured during the course of an acute systemic infection in a single patient in which both a hypermutator phenotype and ceftazidime-avibactam (CZA) resistance rapidly emerged in vivo. Early-course isolates were susceptible to CZA, but following a 7-day period of negative blood cultures, bacteremia recurred and both blood and respiratory cultures grew CZA-resistant isolates. Whole-genome sequencing identified 14 point mutations that differentiated 3 early-course from six CZA-resistant isolates. All six CZA-resistant isolates demonstrated a nonsynonymous G548A mutation in the AmpC gene resulting in a G183D substitution and an R646H substitution in the MutS mismatch repair gene at a conserved position in the Q-loop of the nucleotide binding. G183D substitution was previously shown in vitro to confer both CZA and ceftolozane-tazobactam resistance. Mutation accumulation experiments demonstrated a >10-fold elevation in mutation rate in the MutS R646H isolate. We suggest that the hypermutator phenotype facilitated the rapid emergence of CZA resistance in the context of acute infection in a single mutational step.

Scientific Focus Area: Microbiology and Infectious Diseases

This page was last updated on Friday, March 26, 2021